In the United States alone nosocomial bacteremia develops in about 194,000 patients, and of these about 75,000 die. Maki, D. G., 1981, Nosocomial Infect., (Dikson, R. E., Ed.), page 183, Yrke Medical Books, U.S.A. Most of these deaths are attributable to six major gram-negative bacilli, and these are Pseudomonas aeruginosa, Escherichia coli, Proteus, Klebsiella, Enterobacter and Serratia. The current treatment for bacteremia is the administration of antibiotics which, unfortunately, have limited effectiveness.
The precise pathology of bacteremia is not completely elucidated, nevertheless, it is known that bacterial endotoxins, lipopolysaccharides (LPS), are the primary causative agent. LPS consist of at least three significant antigenic regions, the lipid A, core polysaccharide, and O-specific polysaccharide. The latter is also referred to as O-specific chain or simply O-antigen. The O-specific chain region is a long-chain polysaccharide built up from repeating polysaccharide units. The number of polysaccharide units differs among different bacterial species and may vary from one to as many as six or seven monosaccharide units. While the O-specific chain varies among different gram-negative bacteria, the lipid A and core polysaccharides are similar if not identical.
Since LPS plays a key role in sepsis, a variety of approaches has been pursued to neutralize its activity. Presently, there is considerable work which suggest that antibody to LPS will soon be a valuable clinical adjunct to the standard antibiotic therapy.
LPS initiates a cascade of biochemical events that eventually causes the death of the patient. It is widely believed that the second event, after the introduction of LPS, is the production of tumor necrosis factor (TNF) as a result of LPS stimulation of macrophage cells. Thus, considerable effort has been expended to produce neutralizing antibody to TNF, or other molecules that could inhibit its septic effects. It is likely that antibody to TNF will have valuable clinical applications. Tracey, et all., 1987, Nature, 330: 662.
Sepsis caused by gram-negative bacteria is thought to involve activation of the complement system and causes a depletion of various complement component. One component of a complement system, C5a, causes the aggregation of neutrophils and the aggregates are thought to embolize and cause ischemia. Siegel, J., 1981, Ann. Rev. Med., 32: 175. It has been proposed that C5a is thus responsible for the observed organ failure phenomena in sepsis.
C1 is a plasma glycoprotein with a molecular weight of about 105,000 and is a member of the super family of serine protease inhibitors which include such members as .alpha.1-antitrypsin, .alpha.1-antiplasmin, antithrombin III, and plasminogen activator inhibitor types I and II. One mechanism by which the activator components of the complement system are controlled is by the C1 inhibitor. The C1 inhibitor is known to inhibit activating components of the classical pathway of complement (C1r and C1s) and the intrinsic coagulation system (Factor XIa, Factor XIIa, and Kallikrein). Further, C1 inhibitor has been shown to interact with the fibrinolytic components plasmin and tissue plasminogen activator.
C1 inhibitor is susceptible to proteolytic cleavage by so called non-target proteases, particularly lysosomal serine protease elastase. Browere, M. and Harpel, P., 1982, J. Biol. Chem., 257: 9849. This enzyme is released from polymorphonuclear leukocytes and is present in the circulation of septaremic patients. It is thought that the decrease in the concentration of coagulation factors observed in these patients may, in part, be the result of proteolysis by leukocyte elastase of C1 inhibitor. It will be appreciated, that a possible prophylactic/therapeutic approach to treating sepsis would be to genetically engineer C1 inhibitors that are resistant to proteolytic cleavage and administer these to patients that are at risk of contracting sepsis, or that are already septic.
The life threatening nature of sepsis mandates the identification and development of additional therapeutics or prophylactics, both antibody based or otherwise, that may be efficaciously applied in the treatment of sepsis.